Ivabradine-containing pharmaceutical composition

ABSTRACT

The present invention relates to a pharmaceutical composition containing ivabradine or a pharmaceutically acceptable salt thereof. The invention further relates to a method for the preparation of such a composition.

The present invention relates to a pharmaceutical composition containingivabradine or a pharmaceutically acceptable salt thereof. Further, theinvention relates to a method for the preparation of such a composition.

Ivabradine has the chemical designation(S)-3-{3-[(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-ylmethyl)methylamino]propyl}-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-2-one.Ivabradine has the following structural formula (I):

Synthesis routes for the preparation of ivabradine and its use forpreventing and treating various clinical conditions of myocardialischaemia, supraventricular arrhythmias and coronary arterioscleroticepisodes are reported to be disclosed in EP 534 859.

Ivabradine is an active substance reported to have a bradycardiceffectfor the treatment of stable angina pectoris, in particular in patientsfor whom beta-blockers are contraindicated or an intolerance ofbeta-blockers is present. Ivabradine is reported to selectively inhibitthe I_(f)-ion current, which, as an intrinsic pacemaker in the heart,controls the spontaneous diastolic depolarisation in the sino-atrialnode and thus regulates the heart rate. Under physiological conditions,ivabradine, the S-enantiomer of a racemate, is reported to have a verygood solubility (>10 mg/ml).

The prior art apparently discloses administration forms of ivabradine,which release the active substance substantially without a time delay.The administration form Procoralan® (Servier), which is prepared by wetgranulation, releases ivabradine rapidly and almost completely afteroral intake. WO 2003-061662 apparently discloses anivabradine-containing, orally dispersible tablet, which releases theactive substance very rapidly in the mouth.

Moreover, various polymorphic forms of the ivabradine hydrochloride arereported to be described in the state of the art. WO 2005/110993 A1apparently discloses polymorph alpha, WO 2006/092493 A1 apparentlydiscloses polymorph beta, WO 2006/092491 A1 apparently disclosespolymorph beta d (dehydrated). In addition, polymorph gamma, polymorphgamma d, polymorph delta, and polymorph delta d are reported to be knownin the art. In addition, WO2008/065681 apparently reports the so-calledForm I of Ivabradine HCl. WO 2008/146308 A2 apparently disclosesamorphous ivabradine.

Also various salts of ivabradine are apparently known in the art. WO2008/146308 A2 apparently discloses ivabradine oxalate, WO 2009/124940A1 discloses ivabradine hydrobromide.

The problem with the salts and polymorphs of the ivabradine, inparticular the polymorphs of the hydrochloride, is that these salt formsare not sufficiently stable under all conditions. This, in turn can leadto problems in the processing as well as the storage and to undesiredreactions with the excipients employed in the preparation of thepharmaceutical composition.

Thus, it is an object of the present invention to provide apharmaceutical composition in the preparation and later storage of whichthe employed polymorphic form of the active substance is stable.

A further problem with the ivabradine-containing pharmaceuticalcompositions is that the amount of active substance in the formulationto be administered is usually only small. This leads to problems in thepreparation of the corresponding compositions due to possible variationsin content that are for example conditional on separation tendencies ofthe active substances and excipients. Therefore, it is important that atfirst active substances and excipients can be mixed as homogenous aspossible and corresponding mixtures do not separate again during furtherprocessing to the final formulation. An inhomogeneous distribution ofthe active substance can result in undesired side effects up to symptomsof poisoning. Also the bioavailability as well as the effectiveness ofcorresponding formulations may be affected adversely in an inhomogeneousdistribution of the active substance.

It has been shown that neither problems regarding the stability of theemployed polymorphic form of the active substance nor problems regardingthe homogeneous distribution of the active substance in the finalformulation can be solved by simply mixing and compressing theconstituents.

Thus, a further object of the present invention is to provide apharmaceutical composition that ensures a distribution of the activesubstance in the final formulation that is as homogeneous as possible.At the same time, the employed polymorphic form should remain stableboth in the preparation of the composition and the later storage.

Now, it has surprisingly been found that the above-mentioned problemscan be solved in that at least 95% by weight of the active substance inthe pharmaceutical composition have an average particle size in therange of 0.5 μm to 250 μm.

Thus, the present invention relates to a pharmaceutical compositioncontaining ivabradine as active substance or a pharmaceuticallyacceptable salt thereof wherein at least 95% by weight of the activesubstance based on the total weight of the active substance have anaverage particle size in the range of 0.5 μm to 250 μm.

Presently, by “active substance” ivabradine in the form of the free baseor a pharmaceutically acceptable salt thereof is meant. A suitablepharmaceutically acceptable salt is for example the hydrochloride, thehydrobromide, the oxalate, the sulfate, the phosphate, the acetate, thepropionate, however also salts of the ivabradine with propionic acid,maleic acid, fumaric acid, tartaric acid, nitric acid, benzoic acid,methanesulfonic acid, isethionic acid, benzenesulfonic acid, citricacid, toluenesulfonic acid, trifluoroacetic acid, and camphoric acid andalso the lactate, pyruvate, malonate, succinate, glutarate, andascorbate of the ivabradine. Further, the following salts can beemployed: L-aspartate, glutamate, sorbate, acinotate, gluconate,hippurate, and salts of the ivabradine with ethanesulfonic acid,mandelic acid, adipic acid, or sulfamic acid. The salts of theivabradine can be obtained in accordance to methods reported to be knownin the art by reacting the free base of the ivabradine with thecorresponding acid or by the presence of the corresponding acid in thesynthesis of the ivabradine, as reported to be described for example inUS 2005/0228177 A1. Preferred are ivabradine hydrochloride,hydrobromide, and oxalate, particularly preferred is ivabradine adipate.

In particular, if ivabradine is used as adipate salt, the pharmaceuticalcomposition according to the present invention is stable under usualstorage conditions.

The active substance can be present in the pharmaceutical composition ofthe present invention both in the crystalline and amorphous form. Theactive substance includes all polymorphic forms of ivabradine or apharmaceutically acceptable salt thereof, including hydrates andsolvates. Preferably, the active substance is present in the crystallineform.

Ivabradine adipate can be obtained by adding adipic acid, e.g. about oneequivalent, in a suitable solvent, such as ethanol, to a solution ofivabradine in a suitable solvent, such as dichlormethane. Crystallineivabradine adipate product can be obtained by removal of the solvent,e.g. under vacuum at about 40° C. Crystalline ivabradine adipate canalso be obtained by adding a solution of adipic acid in water to asolution of ivabradine in ethanol, and removal of the solvent.

The DSC thermogramm of ivabradine adipate shows a peak at about 115° C.The melting point is in the range of about 113° C. to about 117° C.

Ivabradine adipate is characterized by an XRD pattern having acharacteristic peak at 20.6±0.2 degrees 2-theta, in particular havingcharacteristic peaks at 14.6±0.2, 16.0±0.2, 18.8±0.2, 20.6±0.2,23.2±0.2, 24.3±0.2, 25.9±0.2 and 26.3±0.2 degrees 2-theta, and furtherat 8.6±0.2, 9.6±0.2, 12.1±0.2 and 12.9±0.2 degrees 2-theta. The XRDpattern of ivabradine adipate is shown in FIG. 1.

It has been shown that the uniformity of the content of active substanceof ivabradine-containing pharmaceutical compositions can be ensured whenthe average particle size of the active substance is in the range of 0.5μm to 250 μm. This way, the separation tendency in the preparation ofthe composition is reduced so that the variations in content in thefinished composition can be prevented. Moreover, it has surprisinglyshown that the pharmaceutical composition can be prepared by simplemixing and compressing with correspondingly small active substanceparticles without leading to a change of otherwise instable polymorphicforms of the active substance. This way it is possible to obtain thepharmaceutical composition according to the invention without thenecessity of an otherwise usual and for the commercialivabradine-containing drug Procoralan® used wet granulation by a simpledry processing of the constituents. So, the employment of specialmachines necessary for the wet granulation can be avoided. Moreover, theemployment of solvents for the preparation of the wet mass can beavoided. It is also not necessary to expose the active substance for alonger period to the granulation liquid until the completion of thedrying. In addition, the drying step following the wet granulationrequires additional energy and the active substance is exposed tothermal influences over a longer period. In contrast, using the activesubstance with a particle size in the range of 0.5 μm to 250 μm permitsthe preparation of the pharmaceutical composition according to theinvention by direct compressing or dry compaction in the absence ofsolvents so that the above-mentioned problems in the preparation ofconventional ivabradine-containing formulations are overcome. Thepreparation of the pharmaceutical composition according to the inventionby direct compressing is particularly preferred.

The pharmaceutical composition according to the invention contains atleast 95% by weight, in particular at least 98% by weight of the activesubstance based on the total weight of the active substance in anaverage particle size in the range of 0.5 μm to 250 μM, preferably inthe range of 0.8 μm to 200 μm, in particular in the range of 1 μm to 150μm.

In a further embodiment of the present invention the pharmaceuticalcomposition contains particles of the active substance having an averageparticle size D50 in the range of 1 μm to 70 μm, preferably of 5 μm to50 μm, most preferably of 10 μm to 25 μm.

In a further embodiment of the present invention the pharmaceuticalcomposition contains particles of the active substance having an averageparticle size D90 in the range of 0.5 μm to 250 μm, preferably of 30 μmto 80 μm, most preferably of 40 μm to 60 μm.

The term “particle size” according to the present invention relates tothe maximum diameter of the equivalent product assuming spherical opaqueparticles showing the same light scattering pattern and the samediffraction as the active substance particles. According to theinvention the particle size is determined by means of laser lightdiffraction. The determination of the size distribution results from theanalysis of the diffraction pattern that is obtained if particles areexposed to a monochromatic light beam. The particles refract the lightwith small particles refracting the light in a greater angle than largeparticles. The refracted light is measured by a number of photodetectors arranged in different angles. On the other hand, the lightspectra of the small particles have to be recorded by light-sensitivedetectors in greater angles over the laser beam. Large particles resultin greater intensity maxima with small angles, small particles to weakerintensity maxima with greater angles. Thus, in the laser lightdiffraction the pattern resulting from the interaction of the light withthe particles is used for the determination of the particle size.

The “particle size distribution” is a statistical frequencydistribution. Here, the particles are divided into classes according totheir size.

The particle size distribution of the particle size D50 value includes50% of the particles based on their volume with a particle size smallerthan the D50 value and 50% of the particles based on their volume with aparticle size greater than the D50 value.

The particle size distribution of the particle size D90 value includes90% of the particles based on their volume with a particle size smallerthan the D90 value and 90% of the particles based on their volume with aparticle size greater than the D90 value.

The particle size distribution according to the present invention can bemonomodal or bimodal. In the preferred embodiment of the invention theparticle size distribution of the active substance is monomodal. Theterm “monomodal” relates to the peak resulting in a histogram and/orgraph representing the distribution frequency. Generally, in thegraphical representation of a particle size distribution there areplotted the diameter x on the abscissa and the measure of a set Q on theordinate.

According to the invention the particle size is determined by means oflaser diffractometry. For that, a Mastersizer 2000 by MalvernInstruments having the corresponding sample dispersing unit Hydro S isused. The wet measurement (2500 rpm, ultrasound 10-20 min., shading 5 to20%) takes place in a dispersion of sunflower oil with the particlespacing in the dispersion being about 3-5 times greater than theparticle diameter.

Here, the average particle size of the active substance is determinedaccording to the following method: In principle, the Fraunhoferdiffraction theory is used for particle fractions the particle size ofwhich is significantly greater than the wave length of the laser light.(ISO 13320)

Moreover, the Mie theory defines the secondary scattering caused by therefraction of the light on small particles, as in the internationalrules of the laser diffraction measurement. (ISO 13320)

The determination of the particle size for particles D50 smaller than5.0 μm is carried out according to the Mie method and for particles D50greater than 5.0 μm according to the Fraunhofer method.

In a further aspect of the present invention it has been shown that theseparation tendency of ready-made mixtures containing the activesubstance and the excipients is reduced in the further processing byaddition of an adhesion enhancer. Additionally, it has been shown thatan adhesion enhancer is suitable to stabilize the polymorphic form ofthe employed active substance in compacted or compressed form. By addingthe adhesion enhancer it usually comes to an enlargement of theinterparticle surfaces at which more easily (e.g. in the compressingoperation) contact points can be formed. Moreover, adhesion enhancersare wherein they increase the plasticity of the tabletting mixture so asto form solid tablets during compressing.

Particularly suitable as adhesion enhancers are polymers, fats, waxes,non-polymeric compounds having at least one polar side group. Theemployed adhesion enhancer should be in the solid form at roomtemperature.

In one embodiment of the present invention the employed adhesionenhancer is a polymer that has a glass transition temperature (Tg)of >15° C., preferably 40° C. to 150° C., and in particular 50° C. to100° C. Here, the glass transition temperature is that temperature atwhich the amorphous or partly crystalline polymer changes from the solidto the liquid state. Here, a significant change of physical parameterssuch as hardness and elasticity occurs. Typically, below the glasstransition temperature a polymer is glassy and hard, above the glasstransition temperature it changes into a rubber-like to viscous state.The determination of the glass transition temperature takes place in thecontext of this invention by means of differential scanning calorimetry(DSC). For that, for example a device of Mettler Toledo DSC 1 can beused. It works with a heating rate of 10° C.

The polymer used as the adhesion enhancer preferably has a numberaverage molecular weight of 1,000 g/mol to 500,000 g/mol, more preferredof 2,000 g/mol to 90,000 g/mol. Additionally, the polymer used shouldhave a viscosity of 0.1 mPa/s to 8 mPa/s, preferably of 0.3 mPa/s to 7mPa/s, and in particular of 0.5 mPa/s to 4 mPa/s in a 2% by weightsolution in water, each measured at 25° C.

Preferably, there can be employed hydrophilic polymers as the adhesionenhancers. This refers to polymers having hydrophilic groups, forexample hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate,and quarternary ammonium groups.

According to the invention the polymer used as the adhesion enhancer canbe selected from the group consisting of polysacharides, such ashydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC),ethylcellulose, methylcellulose, hydroxyethyl-cellulose,ethylhydroxyethylcellulose, and hydroxypropylcellulose (HPC),micro-crystalline cellulose, guar gum, alginic acid, alginates,polyvinylpyrrolidone, polyvinylacetates (PVAC), polyvinyl alcohols(PVA), polymers of the acrylic acid and its salts, polyacrylamides,polymethacrylates, vinylpyrrolidone vinylacetate copolymers,polyalkylene glycoles, such as poly(propylene glycol) and polyethyleneglycol, co-blockpolymers of the polyethylene glycol, in particularco-blockpolymers of polyethylene glycol and poly(propylene glycol) aswell as mixtures of two or more of the mentioned polymers.

Preferably used as the adhesion enhancers are polyvinylpyrrolidone,especially having a weight average molecular weight of 10,000 g/mol to60,000 g/mol, in particular 12,000 g/mol to 40,000 g/mol, copolymersfrom vinylpyrrolidone and vinylacetate, in particular having a weightaverage molecular weight of 40,000 g/mol to 70,000 g/mol, polyethyleneglycol, in particular having a weight average molecular weight of 2,000g/mol to 10,000 g/mol, as well as HPMC, in particular having a weightaverage molecular weight of 20,000 g/mol to 90,000 g/mol and/or aproportion of methyl groups of 10% to 35% and/or a proportion of hydroxygroups of 1% to 35%. Further, microcrystalline cellulose can be used, inparticular those having a specific surface area of 0.7 m²/g to 1.4 m²/g.The determination of the specific surface area takes place by means ofthe gas adsorption method in accordance to Brunauer, Emmet and Teller.

Suitable non-polymeric compounds having at least one polar side groupare in particular sugar alcohols and disaccharides, wherein the termsugar alcohols in this case also comprises monosaccharides. Examples ofsuitable sugar alcohols/disaccharides are lactose, mannitol, sorbitol,xylitol, isomalt, glucose, fructose, maltose, and mixtures of two ormore of these compounds.

Alternatively, also waxes such as for example hexadecyl palmitate orcarnauba wax can be used as adhesion enhancers. Also, fats such asglycerol fatty acid esters (e.g., glycerolpalmitate, glycerolbehenate,glycerollaurate, and glycerolstearate) or PEG glycerol fatty acid esterscan be used.

All of the above-mentioned adhesion enhancers can be employed alone oras a mixture of two or more of the mentioned compounds.

It is advantageous if the adhesion enhancer is used in the particulateform and has a volume average particle size (D50) of less than 500 μm,preferably 5 μm to 200 μm.

The weight ratio of the active substance to the adhesion enhancer in thepharmaceutical composition according to the invention can be freelyselected by the skilled person depending on the active substance usedand the adhesion enhancer as well as the desired composition.Preferably, the weight ratio of ivabradine based on the free base toadhesion enhancer is in the range of 10:1 to 1:100, more preferred inthe range of 1:1 to 1:75, more preferred in the range of 1:2 to 1:50,and most preferred in the range of 1:5 to 1:35.

For example, the pharmaceutical composition of the present invention cancontain 1-80% by weight, more preferred 2-60% by weight, in particular2-40% by weight, and especially 3-5% by weight ivabradine, based on thefree base of the active substance and the total weight of thecomposition. Here and in the following, by total weight of thecomposition the weight of the composition without optionally presentfilm coatings is to be understood.

Additionally, the pharmaceutical composition can contain one or morefurther pharmaceutically acceptable excipients, such as e.g. fillers,glidants, flow regulators, release agents, and disintegrants. (“Lexikonder Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete”, editedby H. P. Fiedler, 4^(th) Edition, and “Handbook of PharmaceuticalExcipients”, 3^(rd) Edition, edited by Arthur H. Kibbe, AmericanPharmaceutical Association, Washington, USA, and Pharmaceutical Press,London).

Fillers: The pharmaceutical composition can contain one or morefiller(s). In general, a filler is a substance that increases the bulkvolume of the mixture and thus the size of the resulting pharmaceuticaldosage form. Preferred examples of fillers are lactose and calciumhydrogenphosphate. The filler may be present in a proportion of 0 to 80%by weight, preferred between 10 and 60% by weight of the total weight ofthe composition.

Glidants: The function of the glidant is to ensure that the pelletizingand the ejection take place without much friction between the solids andthe walls. Preferably, the glidant is an alkaline earth metal stearate,e.g. magnesium stearate, or a fatty acid, such as stearic acid.Typically, the glidant is present in an amount of 0 to 2% by weight,preferably between 0.5 and 1.5% by weight of the total weight of thepharmaceutical composition.

Disintegrants: Usually, by a disintegrant is meant a substance that iscapable of breaking up the tablet into smaller pieces as soon as it isin contact with a liquid. Preferred disintegrants are croscarmellosesodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone(crospovidon), sodium carboxymethyl glycolate (e.g. explotab) and sodiumbicarbonate, Typically, the disintegrant is present in an amount of 0 to20% by weight, preferably between 1 and 15% by weight of the totalweight of the composition.

Flow regulators: As the flow regulator there can be used e.g. colloidalsilica. Preferably the flow regulator is present in an amount of 0 to 8%by weight, more preferably in an amount between 0.1 and 3% by weight ofthe total weight of the composition.

Release agents: The release agent can be e.g. talcum and is present inan amount between 0 and 5% by weight, preferably in an amount between0.5 and 3% by the weight of the composition.

Normally, the pharmaceutical composition according to the invention hasa uniformity of the active substance content (content uniformity) of 85%to 115%, preferably 90% to 110%, in particular 95% to 105% of theaverage content. That is, all dosage forms, for example tablets, have acontent of active substance between 85% and 115%, preferably between 90%and 110%, in particular between 95% and 105% of the average activesubstance content. The “content uniformity” is determined according toPh. Eur. 6.0, section 2.9.6.

The pharmaceutical composition of the present invention may be forexample in the form of tablets, granules, or pellets. Here, the granuleor the pellets for example may be present in capsules or sachets.Preferred are tablets that may have a film coating.

In a further preferred embodiment the pharmaceutical composition of thepresent invention is obtainable by dry granulation methods or directcompression methods in the absence of solvents.

Moreover, the present invention relates to a method for the preparationof a pharmaceutical composition as described above wherein the methodcomprises the steps:

-   -   a) obtaining ivabradine or a pharmaceutically acceptable salt        thereof as active substance wherein at least 95% by weight of        the active substance based on the total weight of the active        substance has an average particle size in the range of 0.5 μm to        250 μm, preferably of 0.8 μm to 200 μm, most preferably of 1 μm        to 150 μm; and    -   b) mixing the active substance with one or more pharmaceutically        acceptable excipients.

In the above step a) the active substance is obtained in the mentionedaverage particle size. This can be done in that the active substance iseither provided with the desired particle size or an active substancehaving a greater particle size is at first transferred to particles of asmaller particle size, for example by grinding and/or screening.

In a preferred embodiment of the method according to the invention as anadditional step there is admixed an adhesion enhancer. Suitable adhesionenhancers are the above-mentioned compounds. When an adhesion enhanceris admixed, it is preferred that at least a part of the adhesionenhancer, preferably the complete adhesion enhancer, is (pre-)mixed withthe active substance some time, preferably about 5 to about 30 min.,more preferably about 5 to about 10 min., e.g. about 10 min., beforesubjecting the mixture and optionally further excipients, to furtherprocess steps, e.g. dry granulation or direct compression, preferablydirect compression. It has been surprisingly found that premixing theactive substance and at least part of the adhesion enhancer followed bya short time delay advantageously influences the dissolution profile ofthe obtained composition, in particular of tablets.

Finally, the method according to the invention in a further preferredembodiment comprises the additional step of dry granulation or directcompressing in the absence of solvents, preferably direct compression.Doing so, there may be obtained for example tablets, which if desiredsubsequently can be provided with a film coating.

Preferably, the pharmaceutical composition according to the invention ispresent as a tablet containing ivabradine in an amount preferably of 1mg to 20 mg, more preferred 3 mg to 15 mg, in particular 5 mg to 10 mg,based on ivabradine free base. Thus, object of the invention are inparticular tablets containing 5 mg or 7.5 mg ivabradine, based onivabradine free base.

Preferably, the pharmaceutical composition according to the invention isadministered twice a day.

In a preferred embodiment, the oral administration of the formulationaccording to the invention to a human as a patient leads to a plasmalevel profile which is distinguished by a c_(max) (maximum plasma level)based on a twice daily intake of 5 mg of the active substanceivabradine, in the steady state, of about 5 to 40 ng/ml, preferably 10to 30 ng/ml.

The abovementioned values for the plasma level are preferably meanvalues, obtained by investigations of blood samples of a group of 10test subjects (having an average body weight of 70 kg), thecorresponding blood samples having been taken 0, 1, 2, 4, 6, 8, 12, 24and 48 hours after oral administration of the composition according tothe invention in the steady state. The determination of the plasma levelvalues can preferably be carried out by suitable HPLC-MSMS methods.

Attached FIG. 1 shows an XRD pattern of ivabradine adipate.

FIGS. 2 and 3 show dissolution profiles of the compositions of examples5 and 6, respectively.

XRD samples were analysed on a Bruker-AXS D8 Advance powder X-Raydiffractometer. The measurement conditions were as follows:

-   Measurement in Bragg-Brentano-Geometry on vertical goniometer    (reflection, theta/theta, 435 mm measurement circle diameter)    -   with sample rotation (30 rpm) on 9 position sample stage-   Radiation: Cu Kα1 (1.5406 Å), Tube (Siemens FLCu2K), power 40 kV/40    mA-   Detector: position sensitive detector VANTEC-1    -   3° capture angle (2theta),    -   Anti scatter slit 6.17 mm    -   Detector slit 10.39 mm    -   4° soller slit,    -   primary beam stop (<2° 2theta)-   Monochromator: None-   Second β filter: Ni filter 0.1 mm (0.5%)-   Start angle: 2°-   End Angle: 55°-   Measurement time: 11 min-   Step: 0.016° 2Theta-   Software: EVA (Bruker-AXS, Karlsruhe).

Now, the present invention is explained in more detail with respect tothe following examples without these should be interpreted as beingrestrictive.

EXAMPLE 1 Direct Compression

Ivabradine adipate 6.51 mg Avicel PH101 50.00 mg Calcium hydrogenatephosphate 25.00 mg Sodium croscarmelose 14.91 mg Aerosil 2.58 mgMagnesium Stearate 1.00 mg

Ivabradine adipate together with Avicel PH101 was sieved through a 355μm sieve and pre-mixed for 10 minutes in the tumbling mixer (TurbulaT10B). Subsequently, all the other constituents except for magnesiumstearate were added through the 355 μm sieve and stirred for further 30minutes in the tumbling mixer. After the addition of magnesium stearateit was stirred again for 2 minutes in the tumbling mixer. The finishedmixture was compressed on a rotary press (Riva Piccola) with 7 mm roundbiconvex punch. The tablets had a hardness of about 50-85 N.

EXAMPLE 2 Direct Compression

Ivabradine adipate 6.51 mg Povidon VA 64 10.00 mg Prosolv SMCC 90 64.00mg Sodium Bicarbonate 14.91 mg Talcum 1.00 mg Aerosil 2.58 mg MagnesiumStearate 1.00 mg

Ivabradine adipate together with Povidon VA 64 and Prosolv SMCC 90 wassieved through a 355 μm sieve and pre-mixed for 10 min, in the tumblingmixer (Turbula T10B).

Subsequently, all the other constituents except for magnesium stearatewere added through the 355 μm sieve, and stirred for further 30 min. inthe tumbling mixer. After the addition of magnesium stearate it wasstirred again for 2 min. in the tumbling mixer. The finished mixture wascompressed on a rotary press (Riva Piccola) with 7 mm round biconvexpunch. The tablets had a hardness of about 50-85 N.

EXAMPLE 3 Dry Compacting (Mixture Corresponding to Example 2)

Ivabradine adipate 6.51 mg Povidon VA 64 10.00 mg Prosolv SMCC 90 64.00mg Sodium Bicarbonate 14.91 mg Talcum 1.00 mg Aerosil 2.58 mg MagnesiumStearate 1.00 mg

Ivabradine adipate together with Povidon VA 64 and half of the ProsolvSMCC 90, magnesium stearate, Aerosil and the total amount of sodiumbicarbonate were pre-mixed for 5 min. in the tumbling mixer (TurbulaT10B) and compacted. Subsequently, the material was broken over a 1000μm screen-type mill (Comil), the remaining excipients were added and thecomposition was mixed for 5 min. in the tumbling mixer. The finishedmixture was compressed on a rotary press (Riva Piccola) with 7 mm roundbiconvex punch. The tablets had a hardness of about 50-85 N.

EXAMPLE 4 Direct Compression

Ivabradine HCl form I 5.42 mg Avicel PH101 50.00 mg Calcium hydrogenphosphate 26.09 mg Sodium croscarmelose 14.91 mg Aerosil 2.58 mgMagnesium stearate 1.00 mg

Ivabradine together with Avicel PH101 was pre-mixed for 10 min. in thetumbling mixer (Turbula T10B). Subsequently, all other constituentsexcept for magnesium stearate were added, and stirred for further 30min. in the tumbling mixer. After the addition of magnesium stearate itwas stirred again for 2 min. in the tumbling mixer. The finished mixturewas compressed on a rotary press (Riva Piccola) with 7 mm round biconvexpunch. The tablets had a hardness of about 50-85 N.

EXAMPLE 5 Direct Compression

Ivabradine HCl form I 5.42 mg Povidon VA 64 11.09 mg Prosolv SMCC 9064.00 mg Sodium bicarbonate 14.91 mg Talcum 1.00 mg Aerosil 2.58 mgMagnesum stearate 1.00 mg

Ivabradine together with Povidon VA 64 and Prosolv SMCC 90 was sievedthrough a 355 μm sieve and pre-mixed for 10 min. in the tumbling mixer(Turbula T10B). Subsequently, all other constituents except formagnesium stearate were added through the 355 μm sieve and stirred forfurther 30 min. in the tumbling mixer. After the addition of magnesiumstearate it was stirred again for 2 min. in the tumbling mixer. Thefinished mixture was compressed on a rotary press (Riva Piccola) with 7mm round biconvex punch. The tablets had a hardness of about 50-85 N.

The dissolution profile (conditions: 500 mL 0.1 nHCl pH 1.2, 37° C., 50rpm baskets (USP app. l)) of the tablets of Example 5 is shown in FIG.2.

EXAMPLE 6 Dry Compacting (Mixture According to Example 5)

Ivabradine HCl form I 5.42 mg Povidon VA 64 10.00 mg Prosolv SMCC 9064.00 mg Sodium bicarbonate 15.00 mg Talcum 1.00 mg Aerosil 2.58 mgMagnesum stearate 1.00 mg

Ivabradine and Povidon VA 64 together with half of the Prosolv SMCC 90,magnesium stearate, Aerosil and the total amount of sodium bicarbonatewere pre-mixed for 5 min. in the tumbling mixer (Turbula T10B) andcompacted. Subsequently, the material was broken over a 1000 μmscreen-type mill (Comil), the remaining excipients were added, followedby mixing for 5 min. in the tumbling mixer (Turbula T10B). The finishedmixture was compressed on a rotary press (Riva Piccola) with 7 mm roundbiconvex punch. The tablets had a hardness of about 50-85 N.

The dissolution profile (conditions: 500 mL 0.1 nHCl pH 1.2, 37° C., 50rpm baskets (USP app. I)) of the tablets of Example 6 is shown in FIG.3.

As can be seen in comparison to Example 5 (direct compression), thedirect compression of the same amount of active agents provide animproved dissolution profile compared to the dissolution profile oftablets obtained by compacting.

The pre-mixing of the active agent with the adhesion enhancer for 10min. prior to further processing of the mixture provides an advantageouseffect on the dissolution profile.

EXAMPLE 7 Stability of Ivabradine Adipate Vs. Ivabradine HCl

The stability of ivabradine adipate in comparison to ivabradinehydrochloride form I was investigated at different temperatures andhumidities in open or closed containers for different storage times. Theresults are summarized in the following table.

TABLE Stabilty of Ivabradine adipate versus Ivabradine HCl, form ITemp./humidity, HCl Container, days Form I Adipate 25° C./60% unchangedclosed, 33 d 25° C./60% unchanged closed, 57 d 25° C./60% β + open, 33 dunident. cryst. phase 25° C./60% unchanged open, 57 d 30° C./65%unchanged closed, 33 d 30° C./65% unchanged closed, 57 d 30° C./65% βopen, 33 d 30° C./65% unchanged open, 57 d 40° C./75% unchanged closed,33 d 40° C./75% unchanged closed, 57 d 40° C./75% β open, 33 d 40°C./75% unchanged open, 57 d Particle size D50 in μm 19.10 18.35 Particlesize D90 in μm 44.11 52.71

Ivabradine adipate according to the present invention is stable atvarious conditions. The ivabradine HCl form I undergoes phase transitioninto ivabradine HCl, form beta, or form d, in particular in opencontainers.

1. A pharmaceutical composition containing ivabradine adipate as activesubstance, wherein at least 95% by weight of the active substance basedon the total weight of the active substance has an average particle sizein the range of 0.5 mm to 250 mm.
 2. The pharmaceutical compositionaccording to claim 1 wherein at least 95% by weight of the activesubstance based on the total weight of the active substance has anaverage particle size in the range of 1 mm to 150 mm.
 3. Thepharmaceutical composition according to claim 1, wherein the compositionadditionally contains at least one adhesion enhancer.
 4. Thepharmaceutical composition according to claim 3, wherein the adhesionenhancer is selected from the group consisting of polymers, fats, waxes,and non-polymeric compounds having at least one polar side group.
 5. Thepharmaceutical composition according to claim 4, wherein the polymer isselected from the group consisting of polysaccharides, microcrystallinecellulose, guar gum, alginic acid, alginates, polyvinylpyrrolidone,polyvinylacetates, polyvinyl alcohols, polymers of the acrylic acid andits salts, polyacrylamides, polymethacrylates, vinylpyrrolidonevinylacetate copolymers, polyalkylene glycols, co-block polymers ofpolyethylene glycol, and mixtures comprising two or more of theafore-mentioned polymers.
 6. The pharmaceutical composition according toclaim 5, wherein the polymer is selected from the group consisting ofpolyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate,polyethylene glycols, hydroxypropylmethylcellulose, microcrystallinecellulose and mixtures comprising two or more of the afore-mentionedpolymers.
 7. The pharmaceutical composition according to claim 4,wherein the non-polymeric compounds having at least one polar side groupare selected from the group consisting of sugar alcohols anddisaccharides.
 8. The pharmaceutical composition according to claim 7,wherein the sugar alcohol or disaccharide is selected from the groupconsisting of lactose, mannitol, sorbitol, xylitol, isomalt, glucose,fructose, maltose and mixtures comprising two or more of theafore-mentioned sugar alcohols and disaccharides.
 9. The pharmaceuticalcomposition according to claim 3, wherein the weight ratio of ivabradineadipate based on the free base to adhesion enhancer is in the range of10:1 to 1:100.
 10. The pharmaceutical composition according to claim 3,wherein the adhesion enhancer has a volume average particle size D50 of<500 mm.
 11. The pharmaceutical composition according to claim 1,wherein the composition is obtained by a direct compression method inthe absence of a solvent.
 12. The pharmaceutical composition accordingto claim 1, wherein the composition is in the form of an optionallyfilm-coated tablet.
 13. A method for the preparation of a pharmaceuticalcomposition according to claim 1, said method comprising the steps of:a) obtaining ivabradine adipate as active substance wherein at least 95%by weight of the active substance based on the total weight of theactive substance has an average particle size in the range of 0.5 mm to250 mm; and b) mixing the active substance with one or morepharmaceutically acceptable excipients.
 14. The method according toclaim 13, further comprising the additional step of mixing the activesubstance and excipients with an adhesion enhancer.
 15. The methodaccording to claim 13, further comprising the additional step ofdirectly compressing the mixture that results from step (b) in theabsence of a solvent.
 16. The pharmaceutical composition according toclaim 5, wherein the polymer is a polysaccharides selected from thegroup consisting of hydroxypropylmethylcellulose,carboxymethylcellulose, ethylcellulose, methylcellulose,hydroxyethylcellulose, ethylhydroxyethylcellulose, andhydroxypropylcellulose.
 17. The pharmaceutical composition according toclaim 5, wherein the polymer is a polyalkylene glycol selected from thegroup consisting of poly(propylene glycol) and polyethylene glycol. 18.The pharmaceutical composition according to claim 5, wherein the polymeris a co-block polymer of the polyethylene glycol and poly(propyleneglycol).
 19. The pharmaceutical composition according to claim 9,wherein the weight ratio of ivabradine adipate based on the free base toadhesion enhancer is in the range of 1:5 to 1:35.
 20. The pharmaceuticalcomposition according to claim 10, wherein the adhesion enhancer has avolume average particle size D50 in the range of 5 mm to 200 mm.